Process for the preparation of 7alpha-alkylated 19-norsteroids

ABSTRACT

Processes useful in the preparation of pharmaceutical compounds such as fulvestrant and processes for the preparation of fulvestrant.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.11/192,071 filed Jul. 27, 2005, which claims the benefit of U.S.provisional application Ser. Nos. 60/591,689, filed Jul. 27, 2004;60/600,292, filed Aug. 9, 2004; and 60/633,927, filed Dec. 6, 2004, thecontents of which are incorporated herein in their entirety

FIELD OF THE INVENTION

The invention relates to a new processes useful in the preparation ofpharmaceutical compounds such as fulvestrant.

BACKGROUND

There is a growing recognition of the need for effective therapeuticstrategies to treat breast cancer patients that are less toxic thanchemotherapy. Since the discovery of the hormonal dependency of manybreast cancers, endocrine therapy has been extensively investigated.

Fulvestrant is a pure antiestrogen that represent a significantbreakthrough in the treatment of breast cancer. Despite its pureantagonist activity, studies on ovariectomized rats have confirmed thatfulvestrant, in contrast to Tamoxifen which acts like estrogen to reduceperiosteal bone formation, does not alter estrogen-like orantiestrogenic effects. Fulvestrant also has some distinct advantages ontarget organs other than breast tissue.

Fulvestrant is a steroidal pure antiestrogen with a chemical structuresimilar to estradiol. Studies of estrogen receptor (ER) function havedemonstrated that estradiol binding to the ER initiate a sequence ofevents. Fulvestrant antagonizes estrogen action by occupying the ER andpreventing estrogen-stimulated gene activation, thus interfering withthe estrogen related processes essential for cell-cycle completion.

-   -   Fulvestrant,        7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]-estra-1,3,5        (10)-triene-3,17β-diol, has the following formula:

WO Patent application No. 02/32922 describes a process for preparing anintermediate compound useful for preparing, e.g. fulvestrant, whichprocess comprises aromatization of a compound, and thereafter ifnecessary or desired, carrying out one or more of the following steps:(i) removing any hydroxy protecting group; (ii) converting a precursorgroup to a different such group.

EP Patent No. 0138504 relates to certain 7α-substituted derivatives ofestradiol and related steroids which possess antioestrogenic activity.U.S. Pat. No. 4,659,516, EP Patent No. 0138504 and Bowler, Steroids1989, 54, 71 describe a process for making steroids such as fulvestrant,by which 1,6-conjugate addition of an alkyl group to anestra-4,6-diene-3-one gave a ratio of 7α- to 7β-epimer of 1.2:1(isolated). In WO 02/92322 it is stated that the ratio of epimersobtained using this process on an industrial scale is 1.9:1.

U.S. Pat. No. 6,288,051 describes 7α-(5-methylaminopentyl)-estratrienes.

There remains a need in the art for improved methods of preparingfluvestrant and other 7α-alkylated 19-norsteroids.

SUMMARY OF THE INVENTION

The invention relates to A compound of formula (I):

wherein

-   -   n is an integer ranging from 3 to 14,    -   R₁ is selected from the group consisting of Br, Cl, I, free base        or a salt form of isothiouronium, or SH;    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is either hydroxy, or a C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

In one embodiment, n is 9, R₁ is Br, R₂, R₃, and R₆ are hydrogens, R₄ ishydroxy and R₅ is methyl.

In one embodiment, n is 9, R₁ is Br, R₂, R₃, and R₆ are hydrogens, R₄ isacetyloxy and R₅ is methyl.

In one embodiment, n is 9, R₁ is a hydrobromide salt of isothiouronium,R₂, R₃, and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl.

In one embodiment, n is 9, R₁ is a hydrobromide salt of isothiouronium,R₂, R₃, and R₆ are hydrogens, R₄ is hydroxy and R₅ is methyl.

In one embodiment, n is 9, R₁ is SH, R₂, R₃, and R₆ are hydrogens, R₄ isacetyloxy and R₅ is methyl.

In one embodiment, n is 9, R₁ is SH, R₂, R₃, and R₆ are hydrogens, R₄ ishydroxy and R₅ is methyl.

The invention also relates to a compound of formula

The invention also relates to a process for preparing the compound offormula (II),

comprising:

-   -   a) combining a 19-nor-androsta-4,6-diene-3-one of formula (III)

-   -    with an etheral solvent, to obtain a solution;    -   b) cooling the solution to a temperature of about −60° C. to        about 30° C.;    -   c) adding to the solution of step b), in a drop-wise manner, a        solution of the compound of formula (IV)

-   -    in an etheral solvent to obtain a reaction mixture;    -   d) quenching the reaction mixture; and    -   e) recovering the compound of formula (II);

wherein

-   -   n is an integer ranging from 3 to 14,    -   X is either O or S;    -   R₁ is a C₁₋₁₀ haloalkyl or a hydroxy protecting group;    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is a C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo; and    -   z is a metal halide of the formula R₇M, wherein        -   M is a metal atom; and        -   R₇ is a halogen atom.

In one embodiment of the process, n is 9, X is O, R₁ istertbutyl-dimethylsilyl (TBDMS), R₂, R₃ and R₆ are hydrogens, R₄ isacetyloxy and R₅ is methyl.

In one embodiment of the process, n is 5, X is O, R₁ is TBDMS, R₃ and R₆are hydrogens, R₄ is acetyloxy and R₅ is methyl.

In one embodiment of the process, n is 9, X is S, R₁ is —(CH₂)₃CF₂CF₃,R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl.

In one embodiment of the process, M is a metal atom selected from thegroup consisting of magnesium, zinc, aluminum, copper, copper-lithiumand titanium.

In one embodiment of the process, M is magnesium.

In one embodiment of the process, R₇ is selected from the groupconsisting of Cl, Br and I.

In one embodiment of the process, R₇ is Br.

In one embodiment of the process, a copper catalyst is a combined instep a) with the 19-nor-androsta-4,6-diene-3-one of formula (III) andthe etheral solvent.

In one embodiment of the process, said copper catalyst is in the form ofCu(I)Y, wherein Y is Cl, Br or I.

In one embodiment of the process, said copper catalyst is Cu(I)Cl.

In one embodiment of the process, the compound of formula (II) obtainedin step e) has a ratio of 7α- to 7β-epimer of about 2.5:1 to about12.1:1.

In one embodiment of the process, the compound of formula (II) obtainedin step e) has a ratio of 7α- to 7β-epimer of about 12.1:1.

In one embodiment of the process, the etheral solvent in step a) isselected from the group consisting of: diethyl ether, THF and glyme.

In one embodiment of the process, said etheral solvent is THF.

In one embodiment of the process, the solution of step b) is cooled to atemperature of about −20° C. to about −10° C.

In one embodiment of the process, the reaction mixture in step d) isquenched by one of the reagents selected from the group consisting of:NH₄Cl, HCl, water, acetic acid and a mixture of NH₄Cl with NH₄OH.

In one embodiment of the process, the reaction mixture is quenched withacetic acid.

In one embodiment of the process, the process further comprisesconverting the compound of formula (II) obtained in step e) tofulvestrant.

The invention further relates to a process for preparing the compound offormula (V),

comprising combining a compound of formula (II)

-   -   with acetonitrile and triphenylphosphine dibromide for a        sufficient amount of time for conversion into the compound of        formula (V);

wherein

-   -   n is an integer ranging from 3 to 14,    -   X is O;    -   R₁ is a hydroxy protecting group;    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is a C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

In one embodiment of the process, n is 9, R₁ is tertbutyl-dimethylsilyl(TBDMS), R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl.

In one embodiment of the process, the compound of formula (II) iscombined with the acetonitrile and triphenylphosphine dibromide at atemperature of about 10° C. to about 12° C.

In one embodiment of the process, the process further comprisesconverting the obtained product to fulvestrant.

The invention further relates to a process for preparing the compound offormula (VI)

wherein R₄ is hydroxy, comprising

-   -   combining the compound of formula (VI), wherein R₄ is a C₁₋₆        acyloxy, with a C₁₋₆ alcohol and mineral acid, at a temperature        of about 50° C. to about 70° C.;

wherein

-   -   n is an integer ranging from 3 to 14,    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

In one embodiment of the process, R₂, R₃ and R₆ are hydrogens, and R₅ ismethyl.

In one embodiment of the process, the mineral acid is HBr.

In one embodiment of the process, the temperature is about 60° C.

In one embodiment of the process, the process further comprisesconverting the obtained product to fulvestrant.

The invention further relates to a process for preparing the compound ofthe formula (I)

comprising combining the compound of formula (VI)

-   -   with a solvent selected from a C₁₋₆ aromatic hydrocarbon, a        straight or branched C₁₋₄ alcohol, a C₁₋₄ alkyl amide and        mixtures thereof and thiourea; and recovering the compound of        formula (I)

wherein

-   -   n is an integer ranging from 3 to 14,    -   R₁ is a free base or a salt form of isothiouronium;    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is either hydroxy or C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

In one embodiment of the process, n is 9, R₁ is a hydrobromide salt ofisothiouronium, R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ ismethyl.

In one embodiment of the process, n is 9, R₁ is a hydrobromide salt ofisothiouronium, R₂, R₃ and R₆ are hydrogens, R₄ is hydroxy and R₅ ismethyl.

In one embodiment of the process, the solvent is selected from the groupconsisting of toluene, xylene, benzene, methanol, ethanol, propanol,isopropanol, butanol, dimethylacetamide and mixtures thereof.

In one embodiment of the process, the solvent is a mixture of tolueneand isopropanol or dimethylacetamide.

In one embodiment of the process, the process further comprisesconverting the obtained product to fulvestrant.

The invention further relates to a process for preparing the compound ofthe formula (VII)

comprising combining compound of the formula (I)

-   -   with a base in the presence of an apolar protic organic solvent        at ambient temperature;

wherein

-   -   n is an integer ranging from 3 to 14,    -   R₁ is a free base or a salt form of isothiouronium;    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is either hydroxy or C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

The process of claim 43, wherein n is 9, R₁ is a hydrobromide salt ofisothiouronium, R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ ismethyl.

In one embodiment of the process, n is 9, R₁ is a hydrobromide salt ofisothiouronium, R₂, R₃ and R₆ are hydrogens, R₄ is hydroxy and R₅ ismethyl.

In one embodiment of the process, the base is an alkali metal base.

In one embodiment of the process, the base is NaOH.

In one embodiment of the process, the aprotic polar organic solvent isdimethylacetamide or acetonitrile.

In one embodiment of the process, said aprotic polar organic solvent isdimethylacetamide.

In one embodiment of the process, the process further comprisesconverting the obtained product to fulvestrant.

The invention further relates to a process for preparing the compound ofthe formula (I)

comprising combining the compound of formula (VII)

-   -   with 4,4,5,5,5-pentafluoropentane-1-ol mesylate at an ambient        temperature; combining the obtained reaction mixture with a base        in the presence of an organic solvent; and recovering the        compound of the formula (I);

wherein

-   -   n is an integer ranging from 3 to 14,    -   R₁ is —S—(CH₂)₃CF₂CF₃    -   R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo;    -   R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆        alkynyl;    -   R₄ is either hydroxy or C₁₋₆ acyloxy;    -   R₅ is C₁₋₆ alkyl; and    -   R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy,        or halo.

The process of claim 51, wherein n is 9, R₂, R₃ and R₆ are hydrogens, R₄is a acetyloxy and R₅ is methyl.

In one embodiment of the process, n is 9, R₂, R₃ and R₆ are hydrogens,R₄ is acetyloxy and R₅ is methyl.

In one embodiment of the process, the base is an alkali metal base.

In one embodiment of the process, the base is KOH.

In one embodiment of the process, the organic solvent is a C₁₋₆ alcohol.

In one embodiment of the process, the organic solvent is methanol.

In one embodiment of the process, wherein the process further comprisesconverting the obtained product to fulvestrant.

The invention further relates to a process for preparing fulvestrantcomprising:

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with C₁₋₆ alcohol and a mineral acid, at atemperature of about 50° C. to about 70° C. to obtain a compound offormula 9354

h) combining compound 9354 with a solvent selected from a C₁₋₆ aromatichydrocarbon, a straight or branched C₁₋₄ alkyl amide and mixturesthereof and thiourea to provide a compound of formula 9388

and recovering compound 9388;

i) combining compound 9388 with a base at ambient temperature to obtaina compound of formula 9389

j) combining compound 9389 with 4,4,5,5,5-pentafluoropenatane-1-olmesylate at an ambient temperature to provide a second reaction mixtureand then combining the second reaction mixture with a base to obtain acompound of formula 9304

and

k) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestrant.

The invention further relates to a process for preparing fulvestrantcomprising:

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with a compound of formula 9383

HS(CH₂)CF₃  9383;

to provide a compound of formula 9363

h) combining at ambient temperature, compound 9363 and a C₁₋₄ alcoholwith an alkali base to obtain compound 9304

and

i) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestrant.

The invention further relates to a process for preparing fulvestrantcomprising

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with a solvent selected from a C₁₋₆ aromatichydrocarbon, a straight or branched C₁₋₄ alkyl amide and mixturesthereof and thiourea to provide a compound of formula 9361

and recovering compound 9361.

h) combining compound 9361 with a base at an ambient temperature toobtain a compound of formula 9362

i) combining compound 9362 with 4,4,5,5,5-pentafluoropenatane-1-olmesylate at ambient temperature to provide a second reaction mixturefollowed by combining the second reaction mixture with a base to obtaina compound of formula 9363

j) combining at ambient temperature compound 9363 and a C₁₋₄ alcoholwith an alkali base to obtain a compound of formula 9304

and

k) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestant.

The invention further relates to a process for preparing fulvestrantcomprising

a) reacting a compound of formula 9363

with a mixture of a C₁₋₄ alcohol and an etheral solvent with an aqueoussolution of an oxidizing agent at a temperature of about 5° C. for about12 hours to provide a compound of formula 9368

and

b) combining at ambient temperature compound 9368 and a C₁₋₄ alcoholwith an alkali base to obtain fulvestant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 2 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 3 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 4 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 5 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 6 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 7 is a schematic showing a method for making an intermediate,useful in the preparation of fluvestrant, according to the method of theinvention.

FIG. 8 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

FIG. 9 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

FIG. 10 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

FIG. 11 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

FIG. 12 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

FIG. 13 is a schematic showing a method for making fluvestrant accordingto the method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The phrase “precursor group,” as used herein, means a functional groupthat can be readily converted to another functional group. Accordingly,the phrase “a group R₄ or a precursor group thereof” means a group R₄ ora group that can be readily converted to R₄. As a representativeexample, esters are a precursor group for an alcohol because the estercan be readily hydrolyzed to provide the alcohol.

The phrase “hydroxy protecting group” or “protected hydroxy,” as usedherein means a group that can replace the hydrogen of a hydroxyl, i.e.,the hydrogen of an —OH group, and then be subsequently be removed andreplaced by a hydrogen to reform the hydroxyl group. The hydroxylprotecting group prevents the hydroxyl from reacting under a given setof conditions, which typically are necessary to perform a reaction atanother part of a molecule. After reaction at the other part of themolecule, the hydroxyl protecting group can be removed to provide thehydroxyl group. A list of suitable hydroxy protecting groups can befound in Protective Groups in Organic Synthesis, Third Edition, JohnWiley, New York 1999. Representative hydroxyl protecting groups include,but are not limited to: alkyl or aryl ethers, silyl ethers and esters.

Representative hydroxyl protecting groups include, but are not limitedto:

methyl ethers including, but not limited to, methoxymethyl;methylthiomethyl; t-butylthiomethyl; (phenyldimethyldiyl)methoxy-methyl;benzyloxymethyl; p-methoxybenzyl-oxymethyl; (4-methoxyphenoxy)methyl;guaiacolmethyl; t-butoxymethyl; 4-pentenyloxymethyl; siloxymethyl;2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl;bis(2-chloroethoxy)methyl; 2-(trimethylsilyl)ethoxymethyl;tetrahydropyran-2-yl; 3-bromotetrahydropyran-2-yl; 1-methoxycyclohexyl;4-methoxy-tetrahydropyran-2-yl; 4-methoxytetrahydrothiopyran-2-yl;4-methoxytetrahydrothio-pyran-2-yl-S,S-dioxido;1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl; 1,4-dioxan-2-yl;tetrahydrofuranyl; tetrahydrothiofuranyl; and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl;

ethyl ethers including, but not limited to, 1-ethoxyethyl;1-(2-chloroethoxy)ethyl; 1-methyl-1-methoxyethyl;1-methyl-1-benzyloxy-2-fluoroethyl; 2,2,2-trichloroethyl;2-trimethylsilylethyl; 2-(phenylselenyl)ethyl; t-butyl; allyl;p-chlorophenyl; p-methoxyphenyl; and 2,4-dinitrophenyl,

benzyl ethers including, but not limited to, benzyl; p-methoxybenzyl;3,4-dimethoxybenzyl; o-nitrobenzyl; p-nitrobenzyl; p-halobenzyl;2,6-dichlorobenzyl; p-cyanobenzyl; p-phenylbenzyl; 2- and 4-picolyl;3-methyl-2-picolyl-N-oxido; diphenylmethyl; p,p′-dinitrobenzhydryl;5-dibenzosuberyl; triphenylmethyl; a-naphthyldiphenylmethyl;p-methoxyphenyldiphenylmethyl; di(p-methoxyphenyl)phenylmethyl;tri(p-methoxyphenyl)methyl;4-(4′-bromo-phenacyloxy)phenyldiphenylmethyl;4,4′1,4″-tris(4,5-dichlorophthalimidophenyl)methyl;4,4′,4″-tris-(levulinoyloxyphenyl)methyl;4,4′,4″-tris(benzoyloxyphenyl)methyl;3-(imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)-methyl;1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl; 9-anthryl;9-(9-phenyl)xanthenyl; 9-(9-phenyl-10-oxo)anthryl;1,3-benzodithiolan-2-yl; and benzisothiazolyl S,S-dioxido;

silyl ethers including, but not limited to, trimethylsilyl;triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl;diethylisopropylsilyl; dimethylthexylsilyl; t-butyldimethylsilyl;t-butyl-diphenylsilyl; tribenzylsilyl; tri-p-xylylsilyl; triphenylsilyl;diphenylmethylsilyl; and t-butylmethoxyphenylsilyl;

esters including, but not limited to, formate; benzoylformate; acetate;chloroacetate; trichloroacetate; methoxyacetate;triphenylmethoxyacetate; phenoxyacetate; p-chlorophenoxyacetate;p-(phosphate)phenylacetate; 3-phenylpropionate; 4-oxopentanoate(levulinate); 4,4-(ethylenedithio)pentanoate; pivaloate; adamantoate;crotonate; 4-methoxycrotonate; benzoate; p-phenylbenzoate; and2,4,6-trimethylbenzoate;

carbonates including, but not limited to, methyl carbonate;9-fluorenyl-methylcarbonate; ethyl carbonate; 2,2,2-trichloroethylcarbonate; 2-(trimethylsilyl)ethyl carbonate; 2-(phenylsulfonyl)ethylcarbonate; 2-(triphenylphosphono)ethyl carbonate; isobutyl carbonate;vinyl carbonate; allyl carbonate; p-nitrophenyl carbonate; benzylcarbonate; p-methoxybenzyl carbonate; 3,4-dimethoxybenzyl carbonate;o-nitrobenzyl carbonate; p-nitrobenzyl carbonate; S-benzylthiocarbonate; 4-ethoxy-1-naphthyl carbonate; and methyldithiocarbonate;

protecting groups with assisted cleavage including, but not limited to,2-iodobenzoate; 4-azidobutyrate; 4-nitro-4-methylpentanoate;o-(dibromomethyl)benzoate; 2-formylbenzenesulfonate;2-(methylthiomethoxy)ethyl carbonate; 4-(methylthiomethoxy)-butyrate;and 2-(methylthiomethoxymethyl)benzoate;

miscellaneous esters including, but not limited to,2,6-dichloro-4-methylphenoxyacetate;2,6-dichloro-4-(1,1,3,3-tetramethyl-butyl)phenoxyacetate;2,4-bis(1,1-dimethylpropyl)-phenoxy-acetate; chlorodiphenylacetate;isobutyrate; monosuccinoate; (E)-2-methyl-2-butenoate (tigloate);o-(methoxycarbonyl)benzoate; p-benzoate; a-naphthoate; nitrate; alkylN,N,N′,N′-tetramethylphosphorodiamidate; N-phenylcarbamate; borate;dimethylphosphinothioyl; and 2,4-dinitrophenyl-sulfenate;

sulfonates including, but not limited to, methanesulfonate (mesylate);benzolsulfonate; and tosylate; and

silyl derivatives including, but not limited to, di-t-butylsilylenegroup; 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative;tetra-t-butoxydisiloxane-1,3-diylidene derivative; cyclic carbonates;cyclic boronates; ethyl boronate; and phenyl boronate.

A preferred hydroxy protecting groups is SiR₈R₉R₁₀, wherein R₈, R₉, andR₁₀ are alkyl or branched alkyl containing 1 to 6 carbon atoms. Mostpreferably, R₈ and R₉ are methyl and R₁₀ is t-butyl.

Throughout this specification the rings of the compounds of theinvention are designated using the lettering conventionally used fordesignating the rings of a steroid as depicted below:

Accordingly, the A ring of a steroid is the most left ring of thecompound of formula as drawn above.

The term “aromatizing,” as used herein, means changing a ring structurethat is not aromatic, i.e., either unsaturated or partially saturated,to a ring systems that is aromatic, i.e., a ring system that has acyclic cloud of 4n+2 delocalized II electrons.

One aspect of the present invention is a compound of formula (I):

wherein

n is an integer ranging from 3 to 14,

R₁ is selected from the group consisting of Br, Cl, I, free base or asalt form of isothiouronium, or SH;

R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy, or halo;

R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

R₄ is either hydroxy, or a C₁₋₆ acyloxy;

R₅ is C₁₋₆ alkyl; and

R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy, or halo.

Preferably, n is 9, R₁ is Br, R₂, R₃, and R₆ are hydrogens, R₄ ishydroxy and R₅ is methyl. Said compound of formula (I) correspond tocompound 9354 in FIG. 7.

Preferably, n is 9, R₁ is Br, R₂, R₃, and R₆ are hydrogens, R₄ isacetyloxy and R₅ is methyl. Said compound of formula (I) correspond tocompound 9342 in FIG. 6.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃,and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl. Said compound offormula (I) correspond to compound 9361 in FIG. 8.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃,and R₆ are hydrogens, R₄ is hydroxy and R₅ is methyl. Said compound offormula (I) correspond to compound 9388 in FIG. 9.

Preferably, n is 9, R₁ is SH, R₂, R₃, and R₆ are hydrogens, R₄ isacetyloxy and R₅ is methyl. Said compound of formula (I) correspond tocompound 9362 in FIG. 8.

Preferably, n is 9, R₁ is SH, R₂, R₃, and R₆ are hydrogens, R₄ ishydroxy and R₅ is methyl. Said compound of formula (I) correspond tocompound 9389 in FIG. 9.

Another aspect of the present invention is a compound of formula

Another aspect of the present invention is a process for preparing thecompound of formula (II),

comprising:

-   -   a) combining a 19-nor-androsta-4,6-diene-3-one of formula (III)

-   -    with an etheral solvent, to obtain a solution; and    -   b) adding to the solution of step a), in a drop-wise manner, a        solution of the compound of formula (IV)

-   -    in an etheral solvent to obtain a reaction mixture.        wherein    -   n is an integer ranging from 3 to 14,    -   X is either O or S;    -   R₁ is a C₁₋₁₀ haloalkyl or a hydroxy protecting group;    -   R₂, R₃, R₅ and R₆ are as defined above;    -   R₄ is a C₁₋₆ acyloxy; and    -   z is a metal halide of the formula R₇M, wherein        -   M is a metal atom; and        -   R₇ is a halogen atom;

In one embodiment, the solution is cooled to a temperature of about −60°C. to about 30° C.

In one embodiment, the method further comprises quenching the reactionmixture.

In one embodiment, the invention further comprises recovering thecompound of formula (II).

After combining the compound of formula (IV) and the compound of formula(III), the resulting reaction mixture can be analyzed using conventionalmethods, known to those skilled in the art, to determine completion ofthe reaction. For example, the reaction mixture may be analyzed by thinlayer chromatography (TLC), high pressure liquid chromatography (HPLC),gas chromatography (GC), mass spectrometry (MS), or nuclear magneticresonance (NMR).

In one embodiment, the addition of the compound of formula (IV) to thesolution of the compound of formula (III) is done over a time period ofat least about 1 minute. Typically, the addition of the compound offormula (IV) to the solution of the compound of formula (III) is doneover a time period of at least about 30 minutes, preferably at leastabout 60 minutes, more preferably at least about 90 minutes, and mostpreferably at least about 120 minutes. Preferably, the addition is slowenough to prevent any substantiative color changes in the mixture. Itwas found that the slower the addition, the better the isomer ratioobtained (other factors being unchanged). The addition time, however,may be governed by practical concerns (such as efficient use ofavailable reactors) and it is not usually worthwhile to extend theaddition period beyond 5 hours.

In another embodiment, addition of the compound of formula (IV) to thesolution of the compound of formula (III) is done at a specified rate,i.e., mol equivalents of compound of formula (IVi) per equivalent ofcompound of formula (III) per time unit. For example, the average rateof adding the compound of formula (IV) to the solution of the compoundof formula (II) can range from about 0.001 mol equivalents to about 1mol equivalents of compound of formula (IV) per equivalent of compoundof formula (III) per minute. Preferably, the average rate of additionranges from about 0.002 to about 0.100 mol equivalents of compound offormula (IV) per equivalent of compound of formula (III) per minute.More preferably, the average rate of addition ranges from about 0.005 toabout 0.020 mol equivalents of compound of formula (IV) per equivalentof compound of formula (III) per minute.

Preferably, n is 9, X is O, R₁ is tertbutyl-dimethylsilyl (TBDMS), R₂,R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl. Said compoundof formula (III) corresponds to Compound 9294 in FIG. 1, said compoundof formula (IV) corresponds to Compound 9318 in FIG. 1, and the obtainedcompound of formula (II) corresponds to Compound 9295 in FIG. 1.

Alternatively, n is 5, X is O, R₁ is TBDMS, R₃ and R₆ are hydrogens, R₄is acetyloxy and R₅ is methyl. Said compound of formula (III)corresponds to Compound 9294 in FIG. 2, said compound of formula (IV)corresponds to Compound 9339 in FIG. 2, and the obtained compound offormula (II) corresponds to Compound 9340 in FIG. 2.

Alternatively, n is 9, X is S, R₁ is —(CH₂)₃CF₂CF₃, R₂, R₃ and R₆ arehydrogens, R₄ is acetyloxy and R₅ is methyl. Said compound of formula(III) corresponds to Compound 9294 in FIG. 3, said compound of formula(IV) corresponds to Compound 9330 in FIG. 3, and the obtained compoundof formula (II) corresponds to Compound 9331 in FIG. 3.

M in the compound of formula (IV) is a metal atom selected from thegroup consisting of magnesium, zinc, aluminum, copper, copper-lithium(i.e., a lithium dialkylcopper reagent), and titanium. The preferredmetal atom is Mg. R₇ is a halogen atom selected from the groupconsisting of Cl, Br and I. Preferably, R₇ is Br. When the metal is Mg,a copper catalyst should be used, preferably of the form Cu(I)Y, whereinY is Cl, Br or I, and most preferably Cu(I)Cl.

The compound of formula (II) obtained by this method has a ratio of 7α-to 70β-epimer of about 2.5:1 to about 12.1:1.

In one embodiment, the compound of formula (II), has a ratio of 7α to 7βepimer (isomer ratio) of at least about 3:1. Preferably, the compound offormula (II) has a 7α to 7β ratio of at least about 7:1. Morepreferably, the compound of formula (II) has a 7α to 7β ratio of atleast about 10:1. Most preferably, the compound of formula (II) has a 7αto 7βratio of at least about 12:1.

The etheral solvent may be selected from the group consisting of:diethyl ether, THF and glyme. The preferred etheral solvent is THF.

Preferably, the solution of step b) is cooled to a temperature of about−20° C. to about −10° C.

The etheral solution of the compound of the formula (IV) is added in adropwise manner, in order to avoid a local accumulation of it. Thereaction mixture is stirred constantly, for the same reason. Thedropwise addition of the compound of formula (IV) is what renders thehigh 7α/7β-epimer ratio.

The reaction mixture in step d) may be quenched by one of the reagentsselected from the group consisting of: NH₄Cl, HCl, water, acetic acidand a mixture of NH₄Cl with NH₄OH. The preferred reagent is acetic acid.

The compound of formula (II) may be recovered by any method known in theart. Preferably, traces of the used catalyst are removed, for example,by reaction with ammonium, followed by separation of the compound offormula (II) from the reaction mixture, for example, by evaporation ofthe solvents. The compound of formula (II) may be purified by anymethods known in the art, such as chromatography.

Compounds 9295 and 9331, obtained as described above, may be furtherconverted to fulvestrant.

Another aspect of the present invention is a process for preparing thecompound of formula (V),

comprising combining a compound of formula (II)

with acetonitrile and triphenylphosphine dibromide for a sufficientamount of time for conversion into the compound of formula (V)wherein

n is an integer ranging from 3 to 14,

X is O;

R₁ is a hydroxy protecting group;

R₂, R₃, R₅ and R₆ are as defined above; and

R₄ is a C₁₋₆ acyloxy;

Preferably, n is 9, X is O, R₁ is tertbutyl-dimethylsilyl (TBDMS), R₂,R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl. Said compoundof formula (II) corresponds to Compound 9295 in FIG. 4, and saidcompound of formula (V) corresponds to Compound 9341 in FIG. 4.

Preferably, the compound of formula (II) is combined with theacetonitrile and triphenylphosphine dibromide at a temperature of about11° C. to about 12° C. The compound of formula (V) may be obtained byany methods known in the art, and then it may be further purified bydissolution in toluene and removal of the by-products formed during thereaction.

The compound of formula (V) may be also prepared via the formation ofintermediates, as depicted in FIG. 5.

Compound 9341, obtained as described above, may be further converted tofulvestrant.

Another aspect of the present invention is a process for preparing thecompound of formula (VI)

wherein R₄ is hydroxy, comprisingcombining the compound of formula (VI), wherein R₄ is a C₁₋₆ acyloxy,with a C₁₋₆ alcohol and mineral acid, at a temperature of about 50° C.to about 70° C.

Preferably, R₂, R₃ and R₆ are hydrogens, and R₅ is methyl. Said compoundof formula (VI), wherein R₄ is a acetyloxy corresponds to Compound 9342in FIG. 7, and said compound of formula (VI) wherein R₄ is hydroxycorresponds to Compound 9354 in FIG. 7.

Preferably, the mineral acid is HBr. Preferably, the temperature of thereaction is about 60° C.

Compound 9354, obtained as described above, may be further converted tofulvestrant.

A further aspect of the present invention is a process for preparing thecompound of the formula (I)

comprising combining the compound of formula (VI)

with a solvent selected from a C₁₋₆ aromatic hydrocarbon, a straight orbranched C₁₋₄ alcohol, a C₁₋₄ alkyl amide and mixtures thereof andthiourea; and recovering the compound of formula (I)wherein

n is an integer ranging from 3 to 14,

R₁ is a free base or a salt form of isothiouronium;

R₂, R₃, R₅ and R₆ are as defined above; and

R₄ is either hydroxy or C₁₋₆ acyloxy.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl. Said compound offormula (VI) corresponds to Compound 9342 in FIG. 8, and said compoundof formula (I) corresponds to Compound 9361 in FIG. 8.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃and R₆ are hydrogens, R₄ is hydroxy and R₅ is methyl. Said compound offormula (VI) corresponds to Compound 9354 in FIG. 9, and said compoundof formula (I) corresponds to Compound 9388 in FIG. 9.

A C₁₋₆ aromatic hydrocarbon may be toluene, xylene or benzene. Astraight or branched C₁₋₄ alcohol may be methanol, ethanol, propanol,isopropanol or butanol. A C₁₋₄ alkyl amide may be dimethylacetamide.Most preferably the solvent a mixture of toluene and isopropanol ordimethylacetamide.

Compounds 9361 and 9388, obtained as described above, may be furtherconverted to fulvestrant.

One aspect of the present invention is a process for preparing thecompound of the formula (VII)

comprising combining a compound of the formula (I)

with a base in the presence of an apolar protic organic solvent atambient temperature;wherein

n is an integer ranging from 3 to 14, R₁ is a free base or a salt formof isothiouronium;

R₂, R₃, R₅ and R₆ are as defined above; and

R₄ is either hydroxy or C₁₋₆ acyloxy.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl. Said compound offormula (VII) corresponds to Compound 9362 in FIG. 8, and said compoundof formula (I) corresponds to Compound 9361 in FIG. 8.

Preferably, n is 9, R₁ is a hydrobromide salt of isothiouronium, R₂, R₃and R₆ are hydrogens, R₄ is hydroxy and R₅ is methyl. Said compound offormula (VII) corresponds to Compound 9389 in FIG. 9, and said compoundof formula (I) corresponds to Compound 9388 in FIG. 9.

Preferably, the base is an alkali metal base such as NaOH and KOH. Mostpreferably, the base is NaOH. The aprotic polar organic solvent may bedimethylacetamide or acetonitrile. Preferably, the aprotic polar organicsolvent is dimethylacetamide.

Compounds 9362 and 9389, obtained as described above, may be furtherconverted to fulvestrant.

Another aspect of the present invention is a process for preparing thecompound of the formula (I)

comprising combining the compound of formula (VII)

with 4,4,5,5,5-pentafluoropentane-1-ol mesylate, followed by combiningthe obtained reaction mixture with a base in the presence of an organicsolvent;wherein

n is an integer ranging from 3 to 14,

R₁ is —S—(CH₂)₃CF₂CF₃

R₂, R₃, R₅ and R₆ are as defined above; and

R₄ is either hydroxy or C₁₋₆ acyloxy.

In one embodiment, the compound of formula (VI) and4,4,5,5,5-pentafluoropentane-1-ol mesylate are contacted at ambienttemperature.

Preferably, n is 9, R₂, R₃ and R₆ are hydrogens, R₄ is a acetyloxy andR₅ is methyl. Said compound of formula (I) corresponds to Compound 9363in FIG. 8, and said compound of formula (VI) corresponds to Compound9362 in FIG. 8.

Preferably, n is 9, R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅is methyl. Said compound of formula (I) corresponds to Compound 9304 inFIG. 9, and said compound of formula (VII) corresponds to Compound 9389in FIG. 9.

Preferably, the base is an alkali metal base such as NaOH and KOH. Mostpreferably, the base is KOH. Preferably, the organic solvent is a C₁₋₆alcohol. Most preferably, the organic solvent is methanol.

Compounds 9363 and 9304, obtained as described above, may be furtherconverted to fulvestrant.

Another aspect of the invention is a process for preparing fulvestrantcomprising

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula

9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with C₁₋₆ alcohol and a mineral acid, at atemperature of about 50° C. to about 70° C. to obtain a compound offormula 9354

h) combining compound 9354 with a compound of formula 9383

HS(CH₂)₃CF₂CF₃  9383;

in the presence of an amide and an alkali base to obtain compound 9304

and

i) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestant.

Fulvestrant can be recovered by any methods known in the art, such asevaporating the solvents, and can be further purified by crystallizationfrom a C₁₋₆ aromatic hydrocarbon.

In one embodiment, the solution of the compound of formula 9318 is addedto the solution of the compound of formula 9294 at a temperature ofabout −60° C. to about 30° C.

Another aspect of the invention is a process for preparing fulvestrantcomprising:

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with C₁₋₆ alcohol and a mineral acid, at atemperature of about 50° C. to about 70° C. to obtain a compound offormula 9354

h) combining compound 9354 with a solvent selected from a C₁₋₆ aromatichydrocarbon, a straight or branched C₁₋₄ alkyl amide and mixturesthereof and thiourea to provide a compound of formula 9388

and recovering compound 9388;

i) combining compound 9388 with a base at ambient temperature to obtaina compound of formula 9389

j) combining compound 9389 with 4,4,5,5,5-pentafluoropenatane-1-olmesylate at an ambient temperature to provide a second reaction mixtureand then combining the second reaction mixture with a base to obtain acompound of formula 9304

and

k) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestant.

Fulvestrant can be recovered by any methods known in the art, such asevaporating the solvents, and can be further purified by crystallizationfrom a C₁₋₆ aromatic hydrocarbon.

In one embodiment, the solution of the compound of formula 9318 is addedto the solution of the compound of formula 9294 at a temperature ofabout −60° C. to about 30° C.

Another aspect of the invention is a process for preparing fulvestrantcomprising:

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with a compound of formula 9383

HS(CH₂)CF₂CF₃  9383;

to provide a compound of formula 9363

h) combining at ambient temperature, compound 9363 and a C₁₋₄ alcoholwith an alkali base to obtain compound 9304

and

i) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestant.

Fulvestrant can be recovered by any methods known in the art, such asevaporating the solvents, and can be further purified by crystallizationfrom a C₁₋₆ aromatic hydrocarbon.

In one embodiment, the solution of the compound of formula 9318 is addedto the solution of the compound of formula 9294 at a temperature ofabout −60° C. to about 30° C.

Another aspect of the invention is a process for preparing fulvestrantcomprising

a) combining compound of formula 9294

with an etheral solvent, to obtain a solution;

b) adding to the solution of step a), in a drop-wise manner, a solutionof the compound of formula 9318

in an etheral solvent to obtain a first reaction mixture comprising acompound of formula 9295;

c) quenching the first reaction mixture;

d) recovering compound 9295;

e) combining compound 9295 with acetonitrile and triphenylphosphinedibromide for a time sufficient to convert compound 9295 into a compoundof formula 9341

f) aromatizing the A ring of compound 9341 by reacting compound 9341with a mixture of lithium bromide and copper bromide in acetonitrile toobtain a compound of formula 9342

g) combining compound 9342 with a solvent selected from a C₁₋₆ aromatichydrocarbon, a straight or branched C₁₋₄ alkyl amide and mixturesthereof and thiourea to provide a compound of formula 9361

and recovering compound 9361.

h) combining compound 9361 with a base at an ambient temperature toobtain a compound of formula 9362

i) combining compound 9362 with 4,4,5,5,5-pentafluoropenatane-1-olmesylate (compound 9360) at ambient temperature to provide a secondreaction mixture followed by combining the second reaction mixture witha base to obtain a compound of formula 9363

j) combining at ambient temperature compound 9363 and a C₁₋₄ alcoholwith an alkali base to obtain a compound of formula 9304

and

k) combining compound 9304 and a mixture of a C₁₋₄ alcohol and anetheral solvent with an aqueous solution of an oxidizing agent at atemperature of about 5° C. for about 12 hours to provide fulvestant.

Fulvestrant can be recovered by any methods known in the art, such asevaporating the solvents, and can be further purified by crystallizationfrom a C₁₋₆ aromatic hydrocarbon.

In one embodiment, the solution of the compound of formula 9318 is addedto the solution of the compound of formula 9294 at a temperature ofabout −60° C. to about 30° C.

Another aspect of the invention is a process for preparing fulvestrantcomprising

a) reacting a compound of formula 9363

with a mixture of a C₁₋₄ alcohol and an etheral solvent with an aqueoussolution of an oxidizing agent at a temperature of about 5° C. for about12 hours to provide a compound of formula 9368

and

b) combining at ambient temperature compound 9368 and a C₁₋₄ alcoholwith an alkali base to obtain fulvestant.

This method is depicted schematically in FIG. 13.

The compound of formula 9363 can be made by any method of the invention.

EXAMPLES Comparative Example Repeating EP 138504

Following the method of Example 1 of EP 138504, to the Grignard reagent,Cp 9318, formed from 24.2 grams of 9-bromo-1-nonanol TBDMS (i.e.,9-(dimethyl-t-butylsiloxy)nonyl bromide), cooled to −30° C., were added6.6 grams of copper (I) iodide. After stirring for 10 minutes a solutionof 10 grams of 17β hydroxy estra 4,6 diene 3 one acetate, Cp 9294 (i.e.,6-dehydro-19-nortestosterone acetate), in tetrahydrofuran was added, andstirring continued for 90 minutes. After quenching with acetic acid, theproduct17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate, Cp 9295, was examined by HPLC analysis and found to have a7α/7βratio of 2.3:1.

Comparative Example Repeating WO 02/32922

Following the method of Example 2 of WO 02/32922, the 7α/7β ratioobtained was 2.5:1.

Example 1 Preparation of the Grignard Reagent Cp 9318(9-(Dimethyl-Tert-Butylsilyloxy)Nonyl Magnesium Bromide)

To a mixture of 100 g of 1-bromononanol, 33 g of imidazole and 250 g ofdimethylformamide was added 70.2 g of tert-butyl-chlorodimethylsilaneand the reaction mixture was stirred for 2 hours.

The mixture was diluted with 750 g of water and 220 g of toluene, andthe phases separated. The aqueous phase was re-extracted with 90 g oftoluene. The combined organic phases were washed with 100 g of water,and evaporated under vacuum at 80°. The residue of 9-bromo-1-nonanolTBDMS was dissolved in 500 g of anhydrous tetrahydrofuran.

In a 2 L flask fitted with stirrer, heating bath, condenser, nitrogenatmosphere, and thermometer 10.88 g of magnesium turnings and 100 g oftetrahydrofuran were charged and heated up to 45°.

A small amount of 9-bromo-1-nonanol TBDMS was added to initiate thereaction, and then the remaining solution was added dropwise at such arate as to maintain the reaction mixture at reflux.

When addition was finished the reaction mixture was refluxed for anotherhour, then cooled to about 40° C. and filtered under nitrogen through asintered glass in-line filter (to remove some residual magnesium) anddiluted to about 1.15 L. The solution of reagent was kept at roomtemperature under nitrogen.

Example 2 Preparation of Cp 9295 from Cp 9294 (Depicted in FIG. 1)

10 grams of nandrolone acetate, Cp 9294 (6 dehydro 17β hydroxy estra 4,6diene 3 one acetate), was dissolved in 60 grams of tetrahydrofuran and1.5 grams of copper (I) chloride added. The suspension was cooled undera nitrogen atmosphere to −20° C. and 117 grams of a ca. 0.39M solutionof the Grignard reagent, Cp 9318, formed from 9-bromo-1-nonanol TBDMS(9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide) was addeddropwise over 120 minutes. 10 grams of acetic acid was then added, andstirring continued for 30 minutes at room temperature. The flask wasthen opened to the atmosphere and a solution of 10 grams of ammoniumchloride plus 15 grams of a 25% ammonium hydroxide solution in 73 gramsof water was added and stirring was continued for 2 hours. The phaseswere separated and the upper phase washed with a solution of 5 gramsammonium chloride in 37 grams of water. The upper phase was separatedand the solvent was evaporated under reduced pressure to provide an oilyresidue which was dissolved in dichloromethane (100 grams) and furtherwashed with 50 grams of water. The lower phase was separated and thesolvent was evaporated under reduced pressure to provide an oil (26.0grams) containing 16.9 grams of17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate, Cp 9295, by HPLC assay (93% of theoretical) having a 7α/7βratio of 12.1:1.

The oil was further purified by chromatography using 200 grams of silicagel, eluting with 5% ethyl acetate in toluene. The main fraction, afterevaporation of the solvent, yielded Cp 9295 as an oil (16.8 grams)containing 15.9 grams of17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate by HPLC assay (87.5%) having an 7-alpha/7-beta ratio of96.4:3.6. A later fraction (0.5 grams) contained mainly the 7-β isomer(7α/7β ratio ca 1:3).

The rate of adding 9-(dimethyl-tert-butylsilyloxy)nonyl magnesiumbromide, Cp 9318 was: 0.041 moles of9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide were added to0.032 moles of nandrolone acetate in 120 minutes. This translates into1.28 mol equivalents in 120 minutes, or an average of ca. 0.011 molequivalents per minute.

Example 3 Preparation of Cp 9295 from Cp 9294 (Depicted in FIG. 1)

10 grams of nandrolone acetate (6 dehydro 17β hydroxy estra 4,6 diene 3one acetate), Cp 9294, was dissolved in 54 grams of tetrahydrofuran and1 gram of copper (I) chloride added. The suspension was cooled undernitrogen atmosphere to −20° C. and 146 grams of a 0.346M solution of9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, Cp 9318, (i.e.,the Grignard reagent from 9-bromo-1-nonanol TBDMS) was added dropwiseover 75 minutes. 10 grams of acetic acid was added and stirring wascontinued for 30 minutes at room temperature. The flask was then openedto the atmosphere and a solution of 10 grams of ammonium chloride plus15 grams of a 25% ammonium hydroxide solution in 73 grams of water wasadded and stirring was continued for 2 hours. The phases were separatedand the upper phase was re-extracted with a solution of 5 grams ammoniumchloride plus 0.5 grams of a 25% ammonium hydroxide solution in 37 gramsof water. The upper phase was separated and the solvent was evaporatedunder reduced pressure to provide an oily residue that contained 16.2grams of17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate, Cp 9295, by HPLC assay (89% of theoretical) having a 7α/7βratio of 9.2:1

Example 4 Preparation of Cp 9295 from Cp 9294 (Depicted in FIG. 1)

5 grams of nandrolone acetate (6 dehydro 17β hydroxy estra 4,6 diene 3one acetate), Cp 9294, was dissolved in 60 grams of tetrahydrofuran and0.5 grams of copper (I) bromide added. The suspension was cooled undernitrogen atmosphere to −15° C. and 90 grams of a ca. 0.39M solution of9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, Cp 9318, (i.e.,the Grignard reagent from 9-bromo-1-nonanol TBDMS) was added dropwiseover 120 minutes. After another hour, 5.4 grams of acetic acid was addedand stirring continued for 60 minutes at room temperature. The flask wasthen opened to the atmosphere and a solution of 7 grams of ammoniumchloride plus 10 grams of a 25% ammonium hydroxide solution in 50 gramsof water was added and stirring was continued for 12 hours. The phaseswere separated and the upper phase washed with a solution of 2 gramsammonium chloride in 10 grams of water. The upper phase was thenseparated and the solvent evaporated under reduced pressure to providean oily residue that was dissolved in dichloromethane (100 grams) andfurther washed with 50 grams of water. The lower phase was separated andthe solvent evaporated under reduced pressure to provide oil, Cp 9295,(18.0 grams) with a 7α/7βratio of 7.1:1 by HPLC.

Example 5 Preparation of Cp 9295 from Cp 9294 (Depicted in FIG. 1)

5 grams of nandrolone acetate (6 dehydro 17β hydroxy estra 4,6 diene 3one acetate, Cp 9294,) was dissolved in 50 grams of tetrahydrofuran and2.5 grams of copper (I) iodide added. The suspension was cooled undernitrogen atmosphere to −20° C. and 85 grams of a ca. 0.30M solution of9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, Cp 9318, (i.e.,the Grignard reagent from 9-bromo-1-nonanol TBDMS) was added dropwiseover 120 minutes while maintaining the temperature of the reactionmixture between −10° C. and −20° C. After the addition of 60 grams ofthe Grignard reagent the reaction was shown by HPLC analysis to beincomplete, but to contain the product17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate, Cp 9295, with a 7α/7β ratio of 8.0:1. After complete additionand another hour of stirring, 4.5 grams of acetic acid was added, andstirring continued for 30 minutes at room temperature. The flask wasthen opened to the atmosphere and a solution of 7.5 grams of ammoniumchloride in 80 grams of water was added and stirring was continued for12 hours. The phases were separated and the upper phase was washed witha solution of 2 grams ammonium chloride in 10 grams of water. The upperphase was separated and the solvent evaporated under reduced pressure toprovide oil (13.9 grams) with a 7α/7β ratio of 7.7:1 by HPLC.

Example 6 Preparation of Cp 9331 from Cp 9294 (Depicted in FIG. 3)

10 grams of nandrolone acetate (6 dehydro 17β hydroxy estra 4,6 diene 3one acetate), Cp 9294, are dissolved in 60 grams of tetrahydrofuran and1.5 grams of copper (I) chloride are added. The suspension is cooledunder nitrogen atmosphere to −20° C., and 117 grams of a ca. 0.39Msolution of 9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl magnesiumbromide, Cp 9330, are added dropwise over 120 minutes. 10 grams ofacetic acid are then added, and stirring continued for 30 minutes atroom temperature. The flask is then opened to the atmosphere and asolution of 10 grams of ammonium chloride plus 15 grams of a 25%ammonium hydroxide solution in 73 grams of water are added and stirringis continued for 2 hours. The phases are separated and the upper phaseis washed with a solution of 5 grams ammonium chloride in 37 grams ofwater. The upper phase is then separated and the solvent evaporated toprovide an oily residue which is dissolved in dichloromethane (100grams) and is further washed with 50 grams of water. Evaporation of thelower phase gives an oil containing17β-hydroxy-7α-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-estr-4-en-3-oneacetate, Cp 9331, with a 7α/7β ratio of 9.1:1 by HPLC assay.

Example 7 Preparation of Cp 9341 from Cp 9295-Direct Synthesis (Depictedin FIG. 4)

190 grams of crude Cp 9295(17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate), prepared from 75 grams of 6-dehydronandrolone acetate usingconditions of Example 4, are dissolved in 100 grams of acetonitrile andadded to a suspension at 10-12° C. of triphenylphosphine dibromide(prepared by addition of 140 grams of bromine to 240 grams oftriphenylphosphine in 1200 grams of acetonitrile). The temperature isallowed to rise to ambient temperature and after 0.5 hours conversioninto Cp 9341 is complete by HPLC. The suspension is diluted with 1000grams of toluene, neutralised with ca. 112 grams of ammonium hydroxidesolution 25%, and the phases are separated. The upper (organic) phase iswashed with water (100 g) and then evaporated to an oily residue. Theresidue is taken up in toluene and stirred at 5-10° C. in order toprecipitate most of the triphenylphosphine oxide by-product. Theby-product is filtered off and rinsed with toluene and the filtratepurified by chromatography on silica gel (1250 grams) eluting withtoluene. Weight of pure Cp 9341 obtained: 87 g.

Example 7 Preparation of Cp 9341 from Cp 9295-Indirect Synthesis(Depicted in FIG. 8)

190 grams of crude Cp 9295(17β-hydroxy-7α-[9-[[1,1-dimethylethyl)dimethylsilyl]oxy]nonyl]-estr-4-en-3-oneacetate), prepared from 75 grams of 6-dehydronandrolone acetate (Cp9294) using conditions of Example 4, are dissolved in 750 grams ofmethanol and cooled to between 5° C. and 10° C. under nitrogen. Thesolution is treated with a solution of hydrochloric acid 32% (15 g) inwater (45 g) and kept at 5° C. to 10° C. for 30-60 minutes. The reactionmixture is neutralised by charging a solution of ammonium hydroxidesolution 25% (15 g) in distilled pyrogenic water (45 g) and evaporatedunder vacuum to an oily residue. The residue was dissolved indichloromethane, extracted with water, and evaporated to an oilyresidue. Weight of crude Cp 9297 obtained: ca. 150 g.

The oily residue is dissolved in dichloromethane (975 g) andtriethylamine (60 g), cooled to between 0° C. and 5° C., and treated atthis temperature with methanesulfonyl chloride (48 g). The temperatureof the reaction mixture is brought to between 20° C.-25° C. and themixture is stirred at this temperature for 30 to 60 minutes.

With starting material absent, a solution of sodium chloride (75 g) inwater (1125 g) is added and the mixture stirred for 2-3 hours at roomtemperature. The phases are separated and the lower (organic) phaseagain extracted with a solution of sodium chloride (75 g) in water (1125g). The lower (organic) phase is evaporated at atmospheric pressure toan oily residue. Weight of crude Cp 9326 obtained: ca. 175 g.

The oily residue is dissolved in acetonitrile (375 g) and lithiumbromide (41.2 g) added. The mixture is heated at 55-60° C. for 1.5-2hours, and then evaporated under vacuum to an oily residue. The residueis dissolved in toluene (650 g) and the solution stirred at 35 to 40° C.with a solution of sodium chloride (75 g) in water (1125 g) for 0.5hours. The phases are separated and the upper (organic) phase is washedwith water (375 g) and then evaporated to an oily residue. Weight ofcrude Cp 9341 obtained: ca. 165 g.

If required, the product may be further purified by chromatography onsilica gel (1120 grams) eluting with toluene. Weight of pure Cp 9341obtained: 95 g.

Example 9 Preparation of Cp 9342 by Aromatization of Cp 9341 (Depictedin FIG. 6)

37 grams of Cp 9341 and 6.15 grams of lithium bromide are dissolved in629 grams of acetonitrile and 18.5 grams of copper (II) bromide added.The mixture was stirred at ambient temperature for 7 hours, and thendiluted with a solution of 74 grams of ammonium chloride in 942 grams ofwater. The mixture is further diluted with 37 grams of ammoniumhydroxide solution 25% and 185 grams of ethyl acetate and left overnightunder agitation in an open flask. The phases are separated and the upper(organic) phase is evaporated to an oily residue, which is dissolved in500 grams of dichloromethane and washed with 370 grams of water. Thephases are separated and the lower (organic) phase is evaporated to anoily residue. Weight of Cp 9342 obtained: 36.5 g

Example 10 Preparation of Cp 9354 from Cp 9342 (Depicted in FIG. 7)

To 61.7 grams of Cp 9342 in 494 grams of methanol was added 123.4 gramsof hydrobromic acid 48% and the mixture was heated at 60° C. for 0.8hours. The mixture was slowly cooled to 5° C. and seeded with a crystalof Cp 9354. After 1 hour the suspension was filtered and the crystalsrinsed with a cold mixture of 100 grams methanol and 30 grams of water.After drying under vacuum at 60° C. to constant weight, 46 grams of Cp9354 were obtained.

Example 11 Preparation of Cp 9360

A solution of 70.5 grams of 4,4,5,5,5-pentafluoropentane-1-ol in 1330grams of dichloromethane was cooled under nitrogen and diluted with 59grams of triethylamine followed by 54.5 grams of methanesulfonylchloride. The solution was kept at 20° C. for 2 hours and then dilutedwith 1000 grams of water and agitated overnight. Evaporation of theorganic phase afforded 109 grams of Cp 9360.

Example 12 Preparation of Cp 9304 from Cp 9342 Via Cp 9361, Cp 9362 andCp 9363 (Depicted in FIG. 8 and Part of FIG. 10)

29 grams of Cp 9342 are heated at 80° C. for 16 hours in 198 grams oftoluene and 99 grams of isopropanol with 5.3 grams (1.25 equivalents) ofthiourea. The reaction mixture is evaporated under vacuum to an oilyresidue which is Cp 9361 that is diluted with 250 grams ofdimethylacetamide, followed by combining with 13.7 g of Cp 9360(prepared in example 11) and treating at room temperature for 1 hourwith 22.3 grams of sodium hydroxide solution 50% to give Cp 9363.Hydrolysis of the 17-acetate group is this carried out by treatment atroom temperature for 1 hour with a solution of 5 grams of potassiumhydroxide in 45 grams of methanol. The reaction mixture is diluted withwater and extracted with a mixture of toluene and ethyl acetate (1:1).Evaporation of the extracts afforded 36 grams of crude Cp 9304.

The crude product was purified by chromatography on silica gel (290grams) eluting with toluene/ethyl acetate (95:5) to give 21 grams ofpure Cp 9304.

Example 13 Preparation of Cp 9304 from Cp 9342 (Depicted in FIG. 10)

40 grams of Cp 9360 (prepared according to Example 11) were heated at80° C. for 16 hours with 14.8 grams of thiourea and 345 grams ofdimethylacetamide to give 400 grams of a 10% solution of Cp 9383.

To 90.7 grams of the 10% solution of Cp 9383 was added a solution of18.5 grams of Cp 9342 in 76 grams of dimethylacetamide and the mixturewas cooled to room temperature and treated with 9 grams of sodiumhydroxide solution 50% for 0.6 hours. After neutralisation with 15 gramsof acetic acid, the reaction mixture was then poured into water andextracted with toluene. Evaporation of the organic phase afforded 30grams of Cp 9363.

30 grams of Cp 9363 were dissolved in 185 grams of methanol undernitrogen and the solution treated for 4 hours at room temperature with asolution of 9.25 grams of potassium hydroxide in methanol. Afterneutralization with 13.9 grams of acetic acid the mixture was evaporatedunder vacuum, then dissolved in dichloromethane, extracted with waterand evaporated to provide crude Cp 9304.

The crude product is purified by chromatography on silica gel elutingwith toluene/ethyl acetate (95:5) to provide purified Cp 9304.

Example 14 Preparation of Cp 9304 from Cp 9354-Indirect Process(Depicted in FIG. 9)

A mixture of 10 grams of Cp 9354 and 1.91 grams of thiourea in 100 gramsof dimethylacetamide (to give Cp 9388) was heated at 80° C. for 16hours, cooled to 20/25° C. and treated with 5.3 grams of Cp 9360(prepared as in example 10) followed by 5.05 grams of sodium hydroxidesolution 50%. After 1 hour the reaction mixture was neutralised with 7.5grams of acetic acid, diluted with water, and extracted withtoluene/ethyl acetate (1:1). Evaporation of the organic phase undervacuum gave an oily residue of Cp 9304.

The crude product is purified by chromatography on silica gel elutingwith toluene/ethyl acetate (95:5) to provide purified Cp 9304.

Example 15 Preparation of Cp 9304 from Cp 9354-Direct Process (Depictedin FIG. 11)

To a solution of 20.5 grams of Cp 9354 in 100 grams of dimethylacetamidewas added 109 grams of a 10% solution of Cp 9383 (prepared from Cp 9382from example 10), followed by 10.3 grams of sodium hydroxide solution50%. After 1 hour the reaction mixture was neutralised with 15 grams ofacetic acid, diluted with water, and extracted with toluene/ethylacetate (1:1). Evaporation of the organic phase under vacuum gave 30grams of Cp 9304. The crude product was purified by chromatography onsilica gel (250 grams) eluting with toluene/ethyl acetate (95:5) to give25.3 grams of pure Cp 9304.

Example 16 Preparation of Fulvestrant (Cp 9305) from Cp 9363-IndirectProcess (Depicted in FIG. 12)

A solution of 40.5 grams of Cp 9363 in 320 grams tetrahydrofuran and 81grams methanol was cooled to 5° C. and treated with a warm solution of27 grams sodium (meta) periodate in 183 grams water. The mixture wasallowed to stand at room temperature overnight, concentrated undervacuum and then dissolved in dichloromethane, extracted with water andevaporated to give 40 grams of Cp 9368 (fulvestrant 17-acetate).

The oily residue of Cp 9368 (40 grams) was dissolved in 320 grams ofmethanol under nitrogen and treated for 3 hours at room temperature witha solution of 20 grams of potassium hydroxide in 128 grams methanol.After neutralisation with 30 grams of acetic acid, the reaction mixturewas concentrated under vacuum and then dissolved in dichloromethane,extracted with water and evaporated. The oily residue was crystallisedfrom 400 grams of toluene, then dried under vacuum to constant weight.26.6 grams of fulvestrant were obtained.

Example 17 Preparation of Fulvestrant (Cp 9305) from Cp 9304-DirectProcess (Depicted in FIG. 9)

A solution of 41 grams of Cp 9304 in 328 grams tetrahydrofuran and 82grams methanol was cooled to 5° C. and treated with a warm solution of27 grams sodium (meta)periodate in 185 grams water. The mixture wasallowed to stand at room temperature overnight, concentrated undervacuum and then dissolved in dichloromethane, extracted with water,evaporated, and crystallised from toluene to give 28 grams of Cp 9305(fulvestrant). Further purification can be effected by recrystallisationfrom ethyl acetate.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosure of whichare incorporated herein by reference.

1-50. (canceled)
 51. A process for preparing the compound of the formula (I)

comprising combining the compound of formula (VII)

with 4,4,5,5,5-pentafluoropentane-1-ol mesylate at an ambient temperature; combining the obtained reaction mixture with a base in the presence of an organic solvent; and recovering the compound of the formula (I); wherein n is an integer ranging from 3 to 14; R₁ is —S—(CH₂)₃CF₂CF₃; R₂ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy, or halo; R₃ is either hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R₄ is either hydroxy or C₁₋₆ acyloxy; R₅ is C₁₋₆ alkyl; and R₆ is either hydrogen, C₁₋₆ alkyl, hydroxyl, protected hydroxy, or halo.
 52. The process of claim 0, wherein n is 9, R₂, R₃ and R₆ are hydrogens, R₄ is a acetyloxy and R₅ is methyl.
 53. The process of claim 0, wherein n is 9, R₂, R₃ and R₆ are hydrogens, R₄ is acetyloxy and R₅ is methyl.
 54. The process of claim 0, wherein the base is an alkali metal base.
 55. The process of claim 0, wherein the base is KOH.
 56. The process of claim 0, wherein the organic solvent is a C₁₋₆ alcohol.
 57. The process of claim 0, wherein the organic solvent is methanol.
 58. The process of any one of claims 0 and 0, further comprising converting the obtained product to fulvestrant. 59-62. (canceled) 